Substituted pyrazinyl-1,2,4-oxadiazoles

ABSTRACT

Novel substituted pyrazinyl-1,2,4-oxadiazoles and processes for preparing the same. The compounds are useful in the treatment of edema and hypertension.

SUMMARY OF THE INVENTION

The novel compounds of this invention are depicted in Formula I and thecorresponding quaternary salts are represented by Formula II. ##STR1##wherein

R is hydrogen or lower alkyl (C₁₋₅) such as methyl, ethyl, isopropyl,n-butyl, n-pentyl;

R¹ is hydrogen or lower alkyl (C₁₋₅) such as methyl, ethyl, isopropyl,n-butyl, n-pentyl;

R² is hydrogen or lower alkyl (C₁₋₅) such as methyl, ethyl, isopropyl,n-butyl, n-pentyl;

R³ is hydrogen or lower alkyl (C₁₋₅) such as methyl, ethyl, isopropyl,n-butyl, n-pentyl;

R and R¹ can be joined to form an alkylene group of from 2-4 carbonatoms such as an ethylene or butylene chain;

R⁴ is lower alkyl (C₁₋₅) such as methyl, ethyl, isopropyl, n-butyl orn-pentyl;

X is halo such as fluoro, chloro, bromo or iodo, cyano or phenyl; and

Y is halide as chloride, bromide or iodide or another suitable anionsuch as methanesulfonate or p-toluenesulfonate.

The preferred compounds of this invention are those compounds ofFormulae I and II wherein

R is hydrogen or methyl;

R¹ is hydrogen or methyl;

R² is hydrogen or methyl;

R³ is hydrogen or methyl;

R⁴ is methyl;

X is halo; and

Y is chloride, bromide or iodide.

Specifically preferred compounds of this invention are

3-Amino-5-[3-amino-5-dimethylamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.

2-Methyl-3-amino-5-[3-amino-5-dimethylamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.

3-Amino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.

2-Methyl-3-amino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.

3-Dimethylamino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.

2-Methyl-3-dimethylamino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.

The compounds of this invention as shown by Formulae I and II and thepreferred compounds discussed above are useful because they possessdiuretic, naturetic and antikaluretic properties and can be used in thetreatment of conditions associated with electrolyte imbalance such as inthe treatment of edema and associated hypertension. Furthermore, thecompounds of this invention differ markedly in their solubilityproperties. Thus, while those compounds of Formula I are soluble innon-polar organic solvents such as toluene, ether and the like, theircounterparts of Formula II dissolve readily in polar mileux such aswater, dimethylsulfoxide, and the like.

The products of this invention can be administered to patients (bothhuman and animal) in the form of pills, tablets, capsules, elixirs,injectable preparations and the like. They can be administered eitherorally or parentally or any other feasible method as known to thoseskilled in the art such as intravenously or in the form of suppositoriesand the like.

The type of formulation to be administered can be comprised of one ormore of the compounds of this invention as the only essential activeingredient of the pharmaceutical formulation. The formulations aremerely combinations of the active ingredient mentioned withpharmaceutically inert carriers and the like. Several pharmaceuticalformulations are prepared as shown in Examples 4 and 5.

The compounds of this invention are advantageously administered at adosage range of from about 5 mg. to about one gram per day or a somewhathigher or lower dosage at the physician's discretion, preferably insubdivided amounts on a 2 to 4 times a day regimen and most preferablyat a dosage range from 10 to 500 mg. per day. It will be realized bythose skilled in the art that the dosage range for any particularpatient (animal or human) will depend upon the severity of the diseasetreated, weight of the patient and any other condition which thephysician or other person skilled in the art will take account of.

The compounds of this invention can be administered as shown aboveeither alone with the general pharmaceutical carriers or in combinationwith other kaluretic diuretics such as, for example in combination withhydrochlorothiazide and the like with pharmaceutical carriers.

Example 6 shows the preparation of a typical combination product. Thecombination dosage in a typical formulation to be administered asdescribed above is 5-100 mg. of a compound of this invention with 50-100mg. of a kaluretic diuretic such as hydrochlorothiazide. Generally agood ratio between the two active ingredients is 1 to 10 (compound ofthis invention to the kaluretic diuretic). The combination products canbe administered in similar dosages as that described above for theadministration of a single compound of this invention. Again, it will berealized that the dosage range for any particular patient will depend onthe severity of the disease being treated, weight of the patient and anyother conditions which the physician or other person skilled in the artwill take account of.

The compounds disclosed in this invention in Formulae I and II and thepreferred compounds can be formed according to one or more of theprocesses described below.

Method A

This method is used for the preparation of compounds of Formula I. Itcan be depicted by the following equation: ##STR2##

In the above equation the radicals R, R¹ and X are as defined previouslyfor Formula I. R⁵ is a straight or branched-chain lower alkyl group withup to 10 carbon atoms and M⁺ is an alkalai metal cation such as lithium,sodium, potassium and the like.

The Method A synthesis involves the reaction of a 2-cyanopyrazine IV,generated from III as indicated in Method A, with an alkalai metalalkoxide, R⁵ O⁻ M⁺, e.g., sodium methoxide, in a suitable alcohol, R⁵OH, e.g., methanol, to give the desired intermediate imino ether V.Other alcohols, R⁵ OH, especially lower aliphatic alcohols and theircorresponding lithium, sodium or potassium alkoxides, may be used toform the desired imino ether V. The reaction is carried out in thechosen solvent for 1 to 36 hours at room temperature or by heating on asteam bath for a lesser time. The intermediate imino ether V is notisolated as such but rather the reaction mixture is rendered neutral bythe addition of an equivalent amount (or a stoichiometric amount) of asuitable acid (like HCl, acetic acid, sulfuric acid, etc.) and treateddirectly with cyanamide in the same solvent. In this way, thecyanoamidine VI is formed within 1 to 24 hours.

In Step B of this method A, the cyanoamidine of formula VI is treated ina suitable solvent such as tetrahydrofuran with an equivalent amount ofhydroxylamine to provide the product which is usually recovered from thereaction mixture by extraction or precipitation with water. The reactioncan be carried out either in a protic (e.g., methanol, ethanol, etc.) oran aprotic (e.g., tetrahydrofuran, dioxane, dimethoxyethane) solvent or,preferably, in a combination of solvents at temperatures ranging fromroom temperature to the boiling point of the solvent(s) for 1 to 36hours. The crude reaction product may be purified by recrystallizationfrom a suitable solvent (e.g., methanol, ethyl acetate and the like) orby chromatography.

Another method for the preparation of compounds of Formula I can beshown by the following equation further referred to as Method B.

Method B ##STR3##

In the above equation, the radicals R, R¹, R², R³ X and M⁺ are asdefined previously for Formula I and in Method A. The radical (Act)* iseither R⁵ (as previously defined) or --C(CH₃)═CHCONHC(CH₃)₃, --CON(C₆H₅)₂ or the like.

Method B involves two steps of which the first is reaction of anactivated pyrazine ester VII with a 1,1-di-substituted hydroxyguanidineto give the N-pyrazinoyl derivative VIII. The starting hydroxyguanidineis added to a stirred suspension of the desired pyrazine ester VII in asuitable solvent like isopropanol, dimethylformamide and the like andthe whole is heated at reflux from 0.5 to 1 hour or stirred at roomtemperature until consumption of the pyrazine ester VII is complete asevidenced by thin layer chromatography. The desired intermediate VIIIcan be isolated by precipitation with water and purified byrecrystallization. Alternatively, the intermediate VIII can be takenwithout isolation directly to the final product by simply extending thetime of reaction in Step A. The title compound I is thus produced by athermal cyclization-dehydration reaction. Other solvents likeN-methylpyrrolidone or N-methylmorpholine may also be used.

In another variation, the 1,2,4-oxadiazide ring of I is formed bytreating an aqueous suspension of the N-pyrazinoyl derivative VIII witha suitable base, M⁺ O⁻ H, such as sodium hydroxide and the like, at roomtemperature in water. Other bases such as lithium or potassiumhydroxide, alkali metal carbonates and alkali metal bicarbonates may besubstituted for sodium hydroxide. Further, the reaction may be carriedout in alcohols such as methanol, ethanol, isopropanol, etc. using thecorresponding alkali metal alkoxide as a base. In addition, aproticsolvents like dioxane, tetrahydrofuran, dimethylformamide etc. may alsobe used to effect this cyclization. In this instance, amines such astriethyl amine, ethyl diisopropylamine,1,5-diazabicyclo[4.3.0]non-5-ene, 1,5-diazabicyclo[5.4.0]undec-5-ene,morpholine, pyridine, etc. can be used as the preferred base. Thereaction is then best carried out at temperatures ranging from 0° to120° but preferably at room temperature for 0.5 to 10 hours. The titlecompound I is isolated either by filtration or by extraction with apolar solvent like methylene chloride or ethylacetate and then ispurified by recrystallization.

The compounds of Formula II can be prepared by the following processknown as Method C. An equation for this method is shown below.

Method C ##STR4##

In the above process the radicals, R, R¹, R², R³, R⁴, X and Y⁻ are asdefined previously for Formulae I and II.

In method C, the 3-substituted-5-(pyrazin-2-yl)-1,2,4-oxadiazole I isdissolved in a suitable solvent like N-methylpyrrolidinone butpreferably N,N-dimethylformamide and treated with a lower alkyl halideR⁴ X, preferably methyl iodide. The resulting solution is allowed tostand at room temperature for 2 to 5 days or at temperatures notexceeding 45° C. for up to 24 hours. The solid product II is collectedby filtration and is purified by recrystallization.

The following examples describe the preparation of certain compoundswhich are illustrative of the novel compounds of this invention, andcertain specific dosage forms suitable for administering the novelcompounds. It is to be understood that the invention is not to belimited to the specific compounds described in the examples or by thespecific reaction condition described for the preparation of thesecompounds or by the specific ingredients included in the pharmaceuticalpreparations, but is to be understood to embrace variations andmodifications thereof which fall within the scope of the appendedclaims.

EXAMPLE 1 Preparation of3-Amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazoleStep A: Preparation ofN-cyano-3-amino-5-dimethylamino-6-chloropyrazine-2-carboxamidine

3-Amino-5-dimethylamino-6-chloropyrazinylnitrile (46.1 g, 0.233 mole) isadded in one portion to a solution of methanol (800 ml) containingsodium methoxide (2.48 g., 0.046 mole). The resulting reaction mixtureis stirred at room temperature for 30 hours, then filtered to removetraces of insoluble material and the filtrate is treated with 2.63 ml(0.046 mole) of acetic acid to make the reaction mixture neutral. Thefiltrate is concentrated to a total volume of approximately 200 ml. Thissolution of the imino ether is then treated in one portion withcyanamide (10.51 g, 0.25 mole) and the resulting clear reaction mixtureis allowed to stand at room temperature. Within 1.5 hours a yellow solidprecipitates. The solid is collected by filtration after 5 hours haveelapsed to give 19.5 g of the desired product. Further concentration ofthe filtrate affords an additional 2.6 g of the product.Recrystallization of the crude product from methanol affords ananalytical sample of the title compound as a bright yellow solid, m.p.223°-224° C.

Elemental analysis for C₈ H₁₀ N₇ Cl: Calc.: C, 40.08; H, 4.21; N, 40.91.Found: C, 40.60; H, 4.22; N, 41.10.

IR(KBr, partial): 3400, 3150, 2190, 1600, 1550, 810, 775 cm⁻¹.

¹³ Cnmr (DMSO-d₆): 40.54, 111.31, 115.76, 119.63, 152.61, 153.48, 165.11ppm.

Step B: Preparation of3-Amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole

To a solution of tetrahydrofuran (250 ml) containing 50 ml of methanoland 12.36 g (51.57 mmole) ofN-cyano-3-amino-5-dimethylamino-6-chloropyrazinecarboxamidine is addedhydroxylamine hydrochloride (6.65 g, 103.13 mmole) and triethylamine(21.56 ml, 154.71 mmole). The resulting reaction mixture is protectedfrom moisture (calcium chloride) and heated to reflux for 6 hours. Thereaction mixture is cooled, poured into water (1 l) and the yellow solidwhich forms is collected by filtration. Concentration of the filtrateaffords more solid which when combined with the first crop yields 12.64g (96%) of the desired product. The reaction product is dried at 60° C.and directly affords analytically pure3-amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole,m.p. 210°-211° C.

Elemental analysis for C₈ H₁₀ N₇ OCl: Calc. C, 37.58; H, 3.94; N, 38.35;Cl, 13.86. Found: C, 37.49; H, 3.84; N, 38.20; Cl, 13.79.

IR(KBr, partial): 1635, 1580, 1540, 1390, 1180, 910, 780 cm⁻¹.

¹³ Cnmr (DMSO-d₆): 40.6, 108.5, 120.7, 151.4, 153.3, 167.8, 170, 1 ppm.

EXAMPLE 2 Preparation of3-Amino-5-(3,5-diamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole Step A:Preparation of3,5-diamino-6-chloro-N-(hydroxyiminoaminomethylene)pyrazine-2-carboxamide

See U.S. Pat. No. 3,577,418, Column 18, lines 5-21.

Step B: Preparation of3-Amino-5-(3,5-diamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole

A suspension of3,5-diamino-6-chloro-N-(hydroxyiminoaminomethylene)pyrazine-2-carboxamide(23.82 g, 0.97 mole) in 200 ml of isopropanol containing 2.3 g. (0.1mole) of sodium is refluxed on a steam bath for 12 hours. The reactionmixture is cooled and filtered to give the title compound as a darkyellow solid. The analytical sample is prepared by dissolving the crudeproduct in warm dimethylformamide and adding water until the solutionbecomes almost turbid. The crystals obtained in this way are collectedand dried in vacuo over phosphorus pentoxide to give the title compoundin pure form as a bright yellow solid, m.p. 278° C., (dec.).

Elemental analysis for C₆ H₆ N₇ O Cl: Calc.: C, 31.66; H, 2.66; N,43.08. Found: C, 31.97; H, 2.71; N, 43.27.

IR(KBr, partial): 3460, 3140, 1600, 1400, 1250, 1050, 880, 760 cm⁻¹.

Dmr (DMSO-d₆): 6.2 (2H, broad S,); 7.35 (4H, broad s)δ.

¹³ Cnmr (DMSO-d₆): 107.27; 120.13, 152.73; 153.22; 167.70, 170.35 ppm.

EXAMPLE 3 Preparation of2-Methyl-3-amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazoliumiodide

To 2 ml of dry dimethylformamide is added 340 mg (1.33 mmole) of3-amino-5-(3-amino-5-dimethylamino-6-chloropyrazin-2-yl)-1,2,4-oxadiazole.The resulting yellow solution is treated with 4 ml (64.3 mmole) ofiodomethane. The homogeneous reaction mixture is protected from moisture(CaCl₂) and allowed to stand at 40° C. overnight. The reaction mixtureis cooled to room temperature and filtered to collect the solid whichprecipitated during the course of the reaction. The solid is washed withether and air dried to afford 470 mg. (88T) of the title compound inpure form; m.p. 300°. The title compound can be further purified, ifdesired, by recrystallization from ethanol to give fine, yellow needles.

ir(KBr, partial): 3075, 1670, 1520, 1465, 1395, 1180, 950 cm⁻¹.

UV_(max) (EtoH): 392 nm.

Pmr (DMSO-d₆): 3.28 (6H, S, N(CH₃)₂), 3.88 (3H, S, N⊕-CH₃), 7.53 (2H,NH₂ pyrazine ring), 9.3 (2H, NH₂, oxadiazole ring)δ.

¹³ Cnmr (DMSO-d₆): 36.43, 41.01, 103.51, 122.67, 153.56, 153.71, 161.59,168.69 ppm.

EXAMPLE 4

Compressed Tablet containing 50 mg. of active ingredient.

    ______________________________________                                                              Per tablet, Mg.                                         ______________________________________                                        3-Amino-5-(3,5-diamino-6-chloro-                                              pyrazin-2-yl)-1,2,4-oxadiazole                                                                        50                                                    Calcium phosphate dibasic                                                                             200                                                   Ethyl cellulose (as 5% solution in ethanol                                                            5                                                       Unmixed granulation   255                                                   Add:                                                                            Starch, corn          14                                                      Magnesium stearate    1                                                                             270                                                   ______________________________________                                    

Directions: Mix the active ingredient above and calcium phosphate andreduce to a No. 60 mesh powder. Granulate with Ethocel in alcohol andpass the wet granulation through a No. 10 screen. Dry the granulation at110° F. for 12-18 hours. Dry grind to a No. 20 mesh. Incorporate the"adds" and compress into tablets each weighing 270 mg.

EXAMPLE 5

Dry filled capsule containing 50 mg. of active ingredient.

    ______________________________________                                                          Per capsule, mg.                                            ______________________________________                                        3-Amino-5-(3,5-diamino-6-chloro-                                              pyrazin-2-yl)-1,2,4-oxadiazole                                                                    50                                                        Lactose             273                                                       Magnesium stearate  2                                                           Mixed powders     325                                                       ______________________________________                                    

Mix the active ingredient above, lactose, and magnesium stearate andreduce to a No. 60 mesh powder. Encapsulate, filling 325 mg. in each No.2 capsule.

The above formulations can be employed to prepare compressed tablets orcapsules of other novel compounds of this invention hereinbeforedescribed.

EXAMPLE 6

Combination dosage form in dry filled capsule.

    ______________________________________                                                          Per capsule, mg.                                            ______________________________________                                        3-Amino-5-(3,5-diamino-6-chloro-                                              pyrazin-2-yl)-1,2,4-oxadiazole                                                                    10                                                        Hydrochlorothiazide 50                                                        Magnesium stearate  2                                                         Lactose             73.5                                                      Mixed powders total 185.51                                                    ______________________________________                                    

Mix all of the above ingredients, reduce to a No. 60 mesh powder andencapsulate filling 105.5 mg. in each No. 2 capsule.

What is claimed is:
 1. A compound of the formula: ##STR5## wherein R ishydrogen or lower alkyl (C₁₋₅),R¹ is hydrogen or lower alkyl (C₁₋₅), R²is hydrogen or lower alkyl (C₁₋₅), R³ is hydrogen or lower alkyl (C₁₋₅),R and R¹ can be joined to form with an alkylene group of from 2-4 carbonatoms, R⁴ is lower alkyl (C₁₋₅) X is halo, cyano or phenyl, and Y⁻ ischloride, bromide or iodide, or a suitable anion.
 2. A compound ofFormulae I and II: ##STR6## wherein R is hydrogen or methyl;R¹ ishydrogen or methyl; R² is hydrogen or methyl; R³ is hydrogen or methyl;R⁴ is methyl; X is halo; and Y⁻ is chloride, bromide or iodide.
 3. Acompound of claim 2 wherein R=R¹ =methyl; R² =R³ =hydrogen; and X=chlorowhich is3-amino-5-[3-amino-5-dimethylamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.4. A compound of claim 2 wherein R=R¹ =R⁴ =methyl; R² =R³ =hydrogen; Xis chloro and Y⁻ is iodide which is2-methyl-3-amino-5-[3-amino-5-dimethylamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.
 5. A compound of claim 2 wherein R=R¹ =R² =R³ =hydrogen and X ischloro which is3-amino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.
 6. Acompound of claim 2 wherein R=R¹ =R² =R³ =hydrogen; R⁴ is methyl; X ischloro and Y⁻ is iodide which is2-methyl-3-amino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.
 7. A compound of claim 2 wherein R=R¹ =hydrogen; R² =R³ =methyland X is chloro which is3-dimethylamino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazole.8. A compound of claim 2 wherein R=R¹ =hydrogen; R² =R³ =R⁴ =methyl; Xis chloro and Y⁻ is iodide which is2-methyl-3-dimethylamino-5-[3,5-diamino-6-chloropyrazin-2-yl]-1,2,4-oxadiazoliumiodide.